Benzo[b]thiophene compounds, intermediates, formulations, and methods

ABSTRACT

This invention relates to the field of pharmaceutical and organic chemistry and provides benzothiophene compounds, intermediates, formulations, and methods.

This application claims benefit of Provisional Application No.60/027,692, filed Oct. 10, 1996.

BACKGROUND OF THE INVENTION

This invention relates to the field of pharmaceutical and organicchemistry and provides benzo[b]thiophene compounds, intermediates,formulations, and methods.

Osteoporosis describes a group of diseases which arises from diverseetiologies, but which are characterized by the net loss of bone mass perunit volume. The consequence of this loss of bone mass and resultingbone fracture is the failure of the skeleton to provide adequate supportfor the body. One of the most common types of osteoporosis is associatedwith menopause. Most women lose from about 20% to about 60% of the bonemass in the trabecular compartment of the bone within 3 to 6 years afterthe cessation of menses. This rapid loss is generally associated with anincrease of bone resorption and formation. However, the resorptive cycleis more dominant and the result is a net loss of bone mass. Osteoporosisis a common and serious disease among postmenopausal women.

There are an estimated 25 million women in the United States alone whoare afflicted with this disease. The results of osteoporosis arepersonally harmful, and also account for a large economic loss due toits chronicity and the need for extensive and long term support(hospitalization and nursing home care) from the disease sequelae. Thisis especially true in more elderly patients. Additionally, althoughosteoporosis is generally not thought of as a life threateningcondition, a 20% to 30% mortality rate is related to hip fractures inelderly women. A large percentage of this mortality rate can be directlyassociated with postmenopausal osteoporosis.

The most generally accepted method for the treatment of postmenopausalosteoporosis is estrogen replacement therapy. Although therapy isgenerally successful, patient compliance with the therapy is low,primarily because estrogen treatment frequently produces undesirableside effects. An additional method of treatment would be theadministration of a bisphosphonate compound, such as, for example,Fosomax® (Merck & Co., Inc.).

Throughout premenopausal time, most women have less incidence ofcardiovascular disease than men of the same age. Following menopause,however, the rate of cardiovascular disease in women slowly increases tomatch the rate seen in men. This loss of protection has been linked tothe loss of estrogen and, in particular, to the loss of estrogen'sability to regulate the levels of serum lipids. The nature of estrogen'sability to regulate serum lipids is not well understood, but evidence todate indicates that estrogen can up regulate the low density lipid (LDL)receptors in the liver to remove excess cholesterol.

It has been reported in the literature that serum lipid levels inpostmenopausal women having estrogen replacement therapy return toconcentrations found in the premenopausal state. Thus, estrogen wouldappear to be a reasonable treatment for this condition. However, theside effects of estrogen replacement therapy are not acceptable to manywomen, thus limiting the use of this therapy. An ideal therapy for thiscondition would be an agent which regulates serum lipid levels in amanner analogous to estrogen, but which is devoid of the side effectsand risks associated with estrogen therapy.

Estrogen dependent cancers are major diseases affecting both women andto a lesser extent men. Cancer cells of this type are dependent on asource of estrogen to maintain the original tumor as well as toproliferate and metastasize to other locations. The most common forms ofestrogen dependent cancer are breast and uterine carcinomas. Currentchemotherapy of these diseases relies primarily on the use ofanti-estrogens, predominately tamoxifen. The use of tamoxifen, althoughefficacious, is not without undesirable side-effects, e.g., estrogenagonist properties, such as uterine hypertrophy and carcinogenicpotential. Compounds of the current invention while showing the same orbetter potential for anti-cancer activity also demonstrate a lowerpotential for estrogen agonist activity.

Thus, it would be a significant contribution to the art to provide novelcompounds useful, for example, in the treatment or prevention of thedisease states as indicated herein.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I ##STR1## whereinR¹ is --COOR⁶, --C.tbd.CH, --CH═CH₂, or --COCH₃ ;

R² is --H, --Cl, --F, C₁ -C₄ alkyl, --OH, --O(C₁ -C₄ alkyl), --OCO(C₁-C₆ alkyl), --O--CO--O(C₁ -C₆ alkyl), --O--CO--AR, --OSO₂ (C₂ -C₆alkyl), or --O--CO--OAR, where AR is optionally substituted phenyl;

R³ and R⁴ are, independently, R² ;

R⁵ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino;

R⁶ is --H or C₁ -C₄ alkyl;

X is --CO-- or --CH₂ --; and

n is 2 or 3;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further relates to pharmaceutical compositionscontaining compounds of formula I and methods for the therapeutic use ofsuch compounds and compositions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention further provides intermediate compounds of formulaII which are novel and useful for preparing the pharmaceutically activecompounds of the present invention, and are shown below. ##STR2##wherein R^(2a), R^(3a), and R^(4a) are, independently, --H, --Cl, --F,C₁ ---C₄ alkyl, or --OR⁷, where R⁷ is a hydroxyl protecting group; and

R⁵, X and n have their previous meanings.

A preferred compound of formula II is[2-[4-(t-Butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.

General terms used in the description of compounds herein described beartheir usual meanings. For example, "C₁ -C₆ alkyl" refers to straight orbranched aliphatic chains of 1 to 6 carbon atoms including moieties suchas methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl,hexyl, isohexyl, and the like. Similarly, the term "--OC₁ -C₄ alkyl"represents a C₁ -C₄ alkyl group attached through an oxygen molecule andinclude moieties such as, for example, methoxy, ethoxy, n-propoxy,isopropoxy, and the like. Of these alkoxy groups, methoxy is highlypreferred in most circumstances.

Optionally substituted phenyl includes phenyl and phenyl substitutedonce or twice with C₁ -C₆ alkyl, C₁ -C₄ alkoxy, hydroxy, nitro, chloro,fluoro, or tri (chloro or fluoro)methyl.

The term, "hydroxyl protecting group (R⁷)" contemplates numerousfunctionalities used in the literature to protect a hydroxyl functionduring a chemical sequence and which can be removed to yield the phenol.Included within this group would be acyls, mesylates, tosylates, benzyl,alkylsilyloxys, --OC₁ -C₄ alkyls, and the like. Numerous reactions forthe formation and removal of such protecting groups are described in anumber of standard works including, for example, Protective Groups inOrganic Chemistry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); andThe Peptides, Vol. I, Schrooder and Lubke, Academic Press (London andNew York, 1965). A preferred hydroxyl protecting group for the currentinvention is tert-butyl-dimethylsilyloxy (TBDMS), (see: examples andpreparations, below).

The term "inhibit" includes its generally accepted meaning whichincludes prohibiting, preventing, restraining, alleviating,ameliorating, and slowing, stopping or reversing progression, severity,or a resultant symptom. As such, the present method includes bothmedical therapeutic and/or prophylactic administration, as appropriate.

The compounds of the current invention are named as derivatives ofcentrally located carbon, i.e., the "--CO--" or "--CH₂ --" moiety informula I, thus derivatives are methanones or methanes, e.g. a compoundof A--CO--B, would be named [A][B]methanone. Further the compounds offormula I are derivatives of benzo[b]thiophene which is named andnumbered according to the Ring Index, The American Chemical Society, asfollows: ##STR3##

The starting material for preparing compounds of the present inventionis a compound of formula III or IIIa. ##STR4## wherein R^(2a), R^(3a),R^(4a), R⁵, and n have their previous meanings.

Compounds of formula III are generally known in the art and are preparedessentially as described by Jones, et al., in U.S. Pat. Nos. 4,400,543and 4,418,068 each of which is herein incorporated by reference. Seealso, Jones, et al., J. Med. Chem., 27, p. 1057-1066 (1984). Thecompounds of formula IIIa are prepared as described by Bryant, et al.,in U.S. Pat. Nos. 5,484,798 and 5,492,921, each of which is hereinincorporated by reference. Compounds of formula III or IIIa, whereR^(2a-4a) are --OR⁷ may be prepared by reacting their hydroxy precursorswith the proper number of equivalents of protecting reagent which willallow the C₆ hydroxyl group to remain unprotected. This protectionsynthesis usually results in a statistical distribution of protectinggroups on the various hydroxyl functions. These products can beseparated by chromatographic techniques to yield the desired compound ofIII or IIIa, i.e., a compound with an unprotected 6-hydroxyl. An exampleof this preparation, using the preferred TBDMS protecting group, isgiven below.

The compounds of formula III or IIIa are converted into their triflateanalogs, i.e., the compounds of formula II, by reaction of the phenolwith a trifluoromethylsulfonoylating agent in the presence of an acidscavenger. Commonly used sulfonoylating reagents would be halides, e.g.,trifluoromethylsulfonoyl-chloride, -bromide, or -iodide, anhydridesmixed or homogeneous, e.g., triflic anhydride, or imides, e.g., N-alkylor aryl trifluoromethylsulfonylimide. A preferred reagent isN-phenyltrifluoromethanesulfonimide.

Acid scavengers used in the synthesis of the compounds of formula IIinclude alkali metal bases, e.g., Na₂ CO₃, K₂ CO₃, etc. or organictertiary amines, e.g., trimethylamine, pyridine, lutidine,triethylamine, etc. A preferred acid scavenger is triethylamine.

This reaction may be run in a variety of inert solvents, such as ether,THF, dioxane, methylene chloride, and the like. Of these, THF ispreferred and especially preferred is the anhydrous form of THF.

The sulfonoylation reaction may be run at temperatures between 0-50° C.,with ambient temperature adequate and most convenient. Under thesereaction conditions, the reaction is usually complete within one totwenty hours. The optimal time can be determined by monitoring theprogress of the reaction via conventional chromatographic techniques,such as tlc.

Application of the chemistry described, supra, enables the preparationof the compounds of formula II. Examples of the compounds of formula IIinclude, but are not limited to:

[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-[3-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[2-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[4-(t-butyldimethylsiiyioxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-[3-chloro-4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[3-(t-butyldimethylsilyloxy)-4-fluorophenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-[2-methyl-4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methanone

[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methane

[2-[3-fluoro-4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-[3,4-di-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[2,4-di-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-[2,3-di-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-[2,3-di-chlorophenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-[4-fluorophenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-[2-methyl-3-fluorophenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-[3-methyl-4-chlorophenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[3,4-di-methoxyphenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-[4-methoxyphenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-[4-methoxyphenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

The triflate compounds of formula II are converted to certain compoundsof formula Ia'-Ic' by a transition metal coupling reaction. Transitionmetals such as, but not limited to, palladium and nickel, in variousoxidation states, are generally employed. Typically, these reactions arerun in inert solvents which would include toluene, DMF, acetonitrile,and the like. Catalytic amounts of phosphorous-bearing ligands are usedto facilitate these reactions, e.g., triarylphosphines,bis-diphenylphosphoalkanes, bis-diphenylphosphinoferrocenes and thelike. A preferred phospho-ligand is bis-1,3-diphenylphosphinopropane.Organic bases are also employed to facilitate the reaction, e.g.,trialkylamines, pyridine, etc. A preferred base is triethylamine. Thetemperature employed in this coupling is that which is sufficient toeffect completion of the reaction, generally, in the range from 50-100°C. The length of time required for the reaction to run to completion istypically from four to seventy-two hours. However, the optimal time canbe determined by monitoring the progress of the reaction viaconventional chromatographic techniques.

When the preferred hydroxyl protecting group (R⁷), i.e., TBDMS, ispresent in a compound of formula II, this protecting group is cleavedduring the coupling reaction and subsequent workup. Thus, the products(Ia'-Ic') are isolated as the free hydroxyl derivatives. This chemistryis illustrated in Scheme I, below. ##STR5## wherein R^(2b), R^(3b), andR^(4b) are, independently, --H, --Cl, --F, C₁ -C₄ alkyl, or --OH; andR⁵, R⁶, n, and X have their previous meanings.

The compounds of formula Ia', where the triflate has been replaced by acarbonyl (acid or ester), are prepared by running the metal couplingreaction in the presence of carbon monoxide and using either water or analcohol as a co-solvent/reactant. The use of water in this reactionleads to the formation of the 6-acid derivatives. The use of an alcohol(R⁶ OH) in this reaction leads to the formation of the esterderivatives. Specific examples of these reactions enabling thepreparation of the compounds of formula Ia' are given below. Furtherinformation regarding this chemistry may be found in: Dolle, et al.,Joural of the Chemical Society, Chemical Communications, 904-905 (1987).An alternate method of preparing the 6-carboxylic acid derivatives wouldbe to hydrolyze one of the esters to the carboxylic acid. Thishydrolysis can be done with either basic or acid catalysis. Basiccatalysis is preferred; especially preferred is the use of LiOH.

Application of the chemical synthesis described, supra, enables thepreparation of the compounds of formula Ia'. Compounds of formula Ia'include, but are not limited to:

[2-(4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-hydroxyphenyl)-6-ethoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-n-butyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-1-propyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-fluorophenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-methoxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(3,4-di-methoxyphenyl)-6-ethyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-methyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-methyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-methoxyphenyl)-6-methyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-fluorophenyl)-6-carbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(2-fluorophenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(2,3-di-fluorophenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(3-methylphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(N,N-dimethylamino)ethoxy]phenyl]methanone

[2-(2-ethylphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanoneand the like.

The compounds of formula Ib', where the triflate has been replaced byacetylene or vinyl, are prepared by running the coupling reaction in thepresence of trimethylsilylacetylene or trimethylsilylethylene. Suchchemistry is illustrated in the examples below. Further informationregarding this chemistry may be found in: Chen, et al., TetrahedronLetters, 27(10), p. 1171-1174 (1986).

Application of the chemical synthesis described, supra, enables thepreparation of the compounds of formula Ib', which include, but are notbe limited to:

[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-hydroxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-fluorophenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-methoxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-methoxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(3,4-di-methoxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3,4-di-methoxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(4-methoxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylcarbonylbenzo[b]thien-3-yl][4-[2-(1-morpholino)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-ethynylcarbonylbenzo[b]thien-3-yl][4-[2-(N,N-di-ethylamino)ethoxy]phenyl]methanone

The compounds of formula Ic', where the triflate has been replaced bythe 6-methylketo function, are prepared by running the coupling reactionin the presence of butylvinylether. The chemistry enabling thepreparation of the compounds of formula Ic' is given below. Furtherinformation regarding this chemistry may be found in: Cabri,et al., J.Med. Chem., 55, p. 3654-3655 (1990).

Application of the chemical synthesis described, supra, enables thepreparation of the compounds of formula Ic', which include, but are notlimited to:

[2-(4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methane

[2-(4-fluorophenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-methoxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-methoxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-(3-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(3,4-di-methoxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3,4-di-methoxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(2-chloro-4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-(3-ethyl-4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(4-methoxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methanone

[2-(3-fluoro-4-hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-hexamethyleneimino)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-acetylcarbonylbenzo[b]thien-3-yl][4-[2-(1-morpholino)ethoxy]phenyl]methanone

[2-(4-hydroxyphenyl)-6-acetylcarbonylbenzo[b]thien-3-yl][4-[2-(N,N-di-ethylamino)ethoxy]phenyl]methanone

Other compounds of formula I are prepared by replacing the 2', 3',and/or 4'-position hydroxy moieties, when present, with a moiety of theformula --O--CO--(C₁ -C₆ alkyl), --O--CO--Ar, or --O--SO₂ --(C₂ -C₆alkyl) via well known procedures. See, e.g., U.S. Pat. Nos. 5,393,763 or5,482,949, each of which is incorporated herein by reference.

For example, when an --O--CO(C₁ -C₆ alkyl) or --O--CO-phenyl group isdesired, a mono-, di-, trihydroxy compound of formula Ia', Ib', or Ic'is reacted with an agent such as acyl chloride, bromide, cyanide, orazide, or with an appropriate anhydride or mixed anhydride. Thereactions are conveniently carried out in a basic solvent such aspyridine, lutidine, quinoline or isoquinoline, or in a tertiary aminesolvent such as triethylamine, tributylamine, methylpiperidine, and thelike. The reaction also may be carried out in an inert solvent such asethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane,dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and thelike, to which at least one equivalent of an acid scavenger, such as atertiary amine, has been added. If desired, acylation catalysts such as4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g.,Haslam, et al., Tetrahedron, 36:2409-2433 (1980).

The present reactions are carried out at moderate temperatures, in therange from about -25° C. to about 100° C., frequently under an inertatmosphere such as nitrogen gas. However, ambient temperature is usuallyadequate for the reaction to run.

Acylation of a 2', 3', and/or 4'-position hydroxy group also may beperformed by acid-catalyzed reactions of the appropriate carboxylicacids in inert organic solvents. Acid catalysts such as sulfuric acid,polyphosphoric acid, methanesulfonic acid, and the like are used.

When a formula I compound is desired in which the 2', 3', and/or4'-position hydroxy group of a formula Ia', Ib', or Ic' compound isconverted to a group of the formula --O--SO₂ --(C₂ -C₆ alkyl), themono-, di-, or trihydroxy compound is reacted with, for example, asulfonic anhydride or a derivative of the appropriate sulfonic acid suchas a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught byKing and Monoir, J. Am. Chem. Soc., 97:2566-2567 (1975). The hydroxycompounds also can be reacted with the appropriate sulfonic anhydride ormixed sulfonic anhydrides. Such reactions are carried out underconditions such as were explained above in the discussion of reactionwith acid halides and the like.

Applying the chemical synthetic schemes, supra, compounds of formula Imay be prepared, and such compounds would include, but not be limitedto:

[2-(4-acetyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-hexanoyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-benzoyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-n-butylsulfonoyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-benzoyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-acetyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-benzoyloxyphenyl)-6-ethoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-propanoyloxyphenyl)-6-n-butyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-n-butylsulfonoyloxyphenyl)-6-1-propyloxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-acetyloxy-4-fluorophenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(2-benzoyloxy-4-methoxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-hydroxy-4-acetyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-hexanoyloxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(4-butanoyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-benzoyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-n-butylsulfonoyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-acetyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-benzoyloxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-butanoyloxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(3-acetyloxy-4-fluorophenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(2-benzoyloxy-4-methoxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-chloro-4-acetyloxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-hydroxy-4-n-butylsulfonoyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-hexanoyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(3,4-di-acetyloxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3,4-di-benzoyloxyphenyl)-6-ethenylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-acetyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-butanoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-benzoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-n-butylsulfonoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(4-acetyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(4-benzoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone

[2-(4-hexanoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methane

[2-(3-acetyloxy-4-fluorophenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(2-fluoro-4-benzoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3-fluoro-4-butanoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-(3-acetyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-pyrridinyl)ethoxy]phenyl]methanone

[2-(2-methyl-4-propanoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

[2-(3,4-di-benzoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

[2-(3,4-di-benzoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methane

[2-(2-chloro-4-pentanoyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methanone

[2-(3-ethyl-4-acetyloxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[3-(1-piperidinyl)propoxy]phenyl]methane

Preferred embodiments of the current invention are[2-(4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanonehydrochloride and[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.

Together, the compounds of formulae Ia', Ib', Ic', and theircorresponding acyl and sulfonoyl derivatives comprise the genus of thecompounds of formula I, are novel, and useful for the pharmacologicmethods herein described.

Although the free-base form of formula I compounds can be used in themethods of the present invention, it is preferred to prepare and use apharmaceutically acceptable salt form. Thus, the compounds used in themethods of this invention primarily form pharmaceutically acceptableacid addition salts with a wide variety of organic and inorganic acids,and include the physiologically acceptable salts which are often used inpharmaceutical chemistry. Such salts are also part of this invention.Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,and the like. Salts derived from organic acids, such as aliphatic monoand dicarboxylic acids, phenyl substituted alkanoic acids,hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids, may also be used. Such pharmaceuticallyacceptable salts thus include acetate, phenylacetate, trifluoroacetate,acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. Preferred salts are thehydrochloride and oxalate salts.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I with an equimolar or excess amountof acid. The reactants are generally combined in a mutual solvent suchas diethyl ether or ethyl acetate. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

The term "solvate" represents an aggregate that comprises one or moremolecules of the solute, such as a formula I compound, with one or moremolecules of solvent.

The following examples are presented to further illustrate thepreparation of compounds of the present invention. It is not intendedthat the invention be limited in scope by reason of any of the followingexamples.

NMR data for the following Examples were generated on a GE 300 MHz NMRinstrument, and anhydrous d-6 DMSO was used as the solvent unlessotherwise indicated.

Preparation 1[2-[4-(t-Butyldimethylsilyloxy)phenyl]-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

A solution was prepared consisting of 10 g (21.1 mmol) of[2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneand 6 g (49.1 mmol) of dimethylaminopyridine in 700 mL of THF-DMF(6:1)(v/v). This solution was stirred for one hour at ambienttemperature and then cooled to 0° C. in an ice bath. To this solutionwas added 2.9 g (19.3 mmol) of tert-butyl-dimethylsilylchloride. Thereaction mixture was stirred under a nitrogen atmosphere and allowed towarm to ambient temperature. After seventy-two hours, the reaction wasquenched with the addition of a saturated solution of aqueous NH₄ Cl.The organic layer was separated and washed with water, brine, andfinally dried by filtration through anhydrous Na₂ SO₄ and evaporated todryness The crude product was triturated with CH₂ Cl₂, allowed to standfor three hours, and filtered to remove unreacted starting material.This resulting product is a mixture of isomers, which are separated bychromatography on a silica gel column eluted with a linear gradientbeginning with CHCl₃ and ending with CHCl₃ --MeOH (19:1)(v/v). Thedesired fractions were determined by tlc, combined, and evaporated todryness. This yielded 5.1 g of the title compound, isolated as a yellowcrystalline solid.

PMR: δ 0.12(s,6H); 0.92(s,9H); 1.46(m,2H); 1.67(m,4H); 2.56(m,5H);2.79(t, J=5.6 Hz, 2H); 4.07(t, J=5.7 Hz, 2H); 6.55(d, J=8.9 Hz, 2H);6.66(d, J=8.5 Hz, 2H); 6.77(dd, J₁ =8.7 Hz, J₂ =2.2 Hz, 1H); 7.17(d,J=2.2 Hz, 1H); 7.20(d, J=8.6 Hz, 3H); 7.44(d, J=8.8 Hz, 1H); 7.63(d,J=8.9 Hz, 2H); MS: m/e=587 (M) FD; EA: Calc. for C₃₄ H₄₁ NO₄ SSi: C,69.47; H, 7.03; N, 2.38 Found: C, 69.19; H, 6.98; N, 2.57.

Preparation 2[2-[4-(t-Butyldimethylsilyloxy)phenyl]-6-trifluoromethanesulfonyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

A solution was prepared of 10 g (17.5 mmol) of[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanonein 100 mL of CH₂ Cl₂, which was placed under a nitrogen atmosphere andcooled to 0° C. in an ice bath. Triethylamine (5 mL, 3.6 g, 35.9 mmol)was added followed by the addition of 7 g (19.5 mmol) ofN-phenyltrifluoromethanesulfonimide. The reaction was allowed to warmslowly to ambient temperature over a period of sixteen hours. Thereaction mixture was filtered and evaporated to a red oil. The crudeproduct was chromatographed on a silica gel column eluted with CH₂ Cl₂.This yielded 11 g of the title compound isolated as a tan amorphoussolid.

PMR: (CDCl₃) δ 0.05 (s, 6H); 0.85(s, 9H); 1.35(m, 2H); 1.55(m, 4H);2.40(m,4H); 2.65(t, J=7 Hz, 2H); 4.00(t, J=7 Hz, 2H); 6.65(m, 4H);7.20(m, 3H); 7.65(d, J=10 Hz, 2H); 7.75(m,2H); MS: m/e=720 (M) FD

EXAMPLE 1[2-(4-Hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneHydrochloride

A reaction mixture was prepared consisting of 1 g (1.4 mmol) of[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethanesulfonyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, 5 mL of triethylamine, 5 mL of MeOH, and 60 mg (0.14 mmol) ofbis-diphenylphosphinopropane in 15 mL of anhydrous DMF. The reaction wasstirred at ambient temperature and purged with electronic-grade carbonmonoxide, and 30 mg (0.14 mmol) of Pd(II) (AcO)₂ was added. The reactionsolution changed color from light orange to dark brown. The reactionmixture was heated to 75° C. under a carbon monoxide atmosphere for sixhours. The reaction was allowed to cool to ambient temperature and thesolvents were removed by evaporation in vacuo. The residue was suspendedin THF and filtered to remove the catalyst and other insolubles. The THFwas removed by evaporation. The residue was dissolved in 100 mL of EtOAcand 100 mL of 1N HCl was added. The reaction was vigorously stirred atambient temperature for two hours. The pH of the aqueous layer wasadjusted to 4-5 with HOAc--NaOAc buffer, and the aqueous layer wasseparated and extracted three times with 100 mL portions of EtOAc. Allthe EtOAc extracts were combined and dried with Na₂ SO₄ and evaporatedto dryness. The crude product was further purified by chromatography ona silica gel column eluted with a linear gradient beginning with CH₂ Cl₂and ending with CH₂ Cl₂ --MeOH (85:15)(v/v). The free base of theproduct was converted to its hydrochloride salt by dissolving theresidue in 50 mL of THF and adding THF saturated with HCl. The productis obtaining by evaporating the volatiles. This yielded 540 mg of thetitle compound isolated as a white powder, mp: 128° C. (dec.).

PMR: δ 1.35-1.90 (m, 6H); 2.90-3.10 (m, 4H); 3.45 (m,2H); 3.95 (s, 3H);4.35 (s br, 2H); 6.80 (d, J=8 Hz, 2H); 7.05 (d J=8 Hz, 2H); 7.35 (d, J=8Hz, 2H); 7.65 (d, J=8 Hz, 1H); 7.80(d J=8 Hz, 2H); 8.00 (d, J=8 Hz, 1H);8.80 (s, 1H); 10.00 (s, 1H); MS: m/e=515 (M-HCl) FD; EA: Calc. for C₃₀H₂₉ NO₅ S-HCl-1.5H₂ O: C, 62.24; H, 5.75; N, 2.42 Found: C, 61.90; H,5.60; N, 2.19.

EXAMPLE 2[2-(4-Hydroxyphenyl)-6-n-butoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

In a manner similar to that used in Example 1, only using n-butanol as areactant, 410 mg of the title compound was prepared as its free base andisolated as a white powder, mp: 87-90° C.

PMR: (CDCl₃) δ 1.05 (t, J=6 Hz, 3H); 1.65 (qnt, J=6 Hz, 2H); 1.80 (s br,2H); 1.90 (sxt, J=6 Hz, 2H); 2.05 (d br, 2H); 2.15-2.30 (m, 2H);2.90-3.05 (m, 2H); 3.50 (s br, 2H); 3.75 (d br, 2H); 4.45-4.55 (m, 4H);6.70 (d, J=10 Hz, 2H); 6.75 (d, J=10 Hz, 2H); 7.15 (d, J=8 Hz, 2H); 7.65(d, J=10 Hz, 2H); 8.25 (q, J₁ =12 Hz, J₂ =8 Hz, 2H); 8.70 (s, 1H); MS:m/e=558 (M-HCl) FD; EA: Calc. for C₃₃ H₃₅ NO₅ S-2H₂ O: C, 66.76; H,6.62; N, 2.36; S, 5.40 Found: C, 66.37; H, 6.04; N, 2.24; S, 5.60.

EXAMPLE 3[2-(4-Hydroxyphenyl)-6-(3-methyl)proxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

In a manner similar to that used in Example 1, only using sec-butanol asa reactant, 430 mg of the title compound was prepared as its free baseand isolated as a white powder, mp: 95-98° C.

PMR: (CDCl₃) δ 1.15 (d, J=6 Hz, 6H); 1.75 (s br, 2H); 1.85-1.95 (m, 1H);2.10 (s br, 3H); 2.15 (sxt, J=5 Hz, 1H); 3.10-3.30 (m, 4H); 3.40 (s br,2H); 4.25 (d, J=7 Hz, 2H); 4.45 (s br, 2H); 6.70 (d, J=10 Hz, 2H); 6.80(d, J=10 Hz, 2H); 7.20 (d, J=8 Hz, 2H); 7.65 (d, J=8 Hz, 2H); 8.15 (q,J₁ =2 Hz, J₂ =8 Hz, 2H); 8.70 (s, 1H); MS: m/e=558 (M-HCl) FD; EA: Calc.for C₃₃ H₃₅ NO₅ S-2H₂ O: C, 66.76; H, 6.62; N, 2.36; S, 5.40 Found: C,66.57; H, 6.06; N, 2.32; S, 5.52.

EXAMPLE 4[2-(4-Hydroxyphenyl)-6-carboxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneHydrochloride

A solution was prepared by dissolving 2 g (4.0 mmol) of[2-(4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanoneand 0.2 g (8.0 mmol) of LiOH in 100 mL of THF and 10 mL of water. Thereaction mixture was heated to reflux for eighteen hours. The reactionwas allowed to cool and the solvents were removed by evaporation. Theresidue was partioned between 300 mL of EtOAc and 300 mL of 1N HCl. Theproduct precipitated out and was removed by filtration and dried. Thisyielded 700 mg of the title compound as a yellow powder.

PMR: δ 1.3-1.5 (m,2H); 1.5-1.6 (m, 4H); 2.4-2.6 (m,4H); 2.7-2.8 (m, 2H);4.1-4.2 (m,2H); 6.75 (d, J=8 Hz, 2H); 6.95 (d, J=8 Hz, 2H); 7.30 (d, J=8Hz, 2H); 7.55 (d, J=8 Hz, 1H); 7.75 (d, J=8 Hz, 2H); 7.95 (d, J=8 Hz,1H); 8.65 (s, 1H); MS: m/e=501 (M⁺ -Cl) FD; EA: Calc. for C₂₉ H₂₇ NO₅S-HCl-1.5H₂ O: C, 61.66; H. 5.53; N, 2.48 Found: 61.91; H, 5.47; N,2.31.

EXAMPLE 5[2-(4-Hydroxyphenyl)-6-acetylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

A solution was prepared consisting of 1 g (1.4 mmol) of[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethamesulfonoylxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,1.1 mL (7.7 mmol) of butylvinylether, 1 mL of triethylamine, 60 mg (0.14mmol) of bis-diphenylphosphinopropane, and 30 mg (0.14 mmol) ofPd(II)(AcO)₂ in 15 mL of anhydrous DMF. The reaction mixture was heatedto 75° C., under a nitrogen atmosphere for five hours. The reactionmixture was allowed to cool and 15 mL of 5 N HCL was added. The reactionmixture was stirred for sixteen hours at ambient temperature. Thereaction mixture was evaporated to dryness, suspended in THF, andfiltered. The product was further purified by chromatography asdescribed in Example 1, supra. This yielded 430 mg of the title compoundas an orange solid, mp: 97-100° C.

PMR: δ 1.40 (s br, 2H); 1.80 (s br, 4H); 2.70 (s, 3H); 3.35 (s br, 4H);3.45 (s br, 2H); 4.40 (s br, 2H); 6.75 (d, J=8 Hz, 2H); 7.00 (d, J=8 Hz,2H); 7.30 (d, J=8 Hz, 2H); 7.55 (d, J=8 Hz, 1H); 7.75 (d, J=8 Hz, 2H);7.90 (d, J=8 Hz, 1H); 8.80 (s, 1H); 10.00 (s, 1H); MS: m/e=499 (M⁺) FD;EA: Calc. for C₃₀ H₂₉ NO₄ S-H₂ O: C, 69.61; H, 6.04; N, 2.71; S, 6.19Found: 69.44; H, 6.20; N, 3.09; S, 5.84.

EXAMPLE 6[2-(4-Hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone

A solution was prepared consisting of 2 g (2.8 mmol) of[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethamesulfonyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone,1.0 mL (0.68 g, 6.9 mmol) of trimethylsilylacetylene, 5 mL oftriethylamine, 120 mg (0.28 mmol) of bis-diphenylphosphinopropane, and60 mg (0.28 mmol) of Pd(II)(AcO)₂ in 20 mL of anhydrous DMF. Thereaction mixture was heated to 75° C. for ten hours, under a nitrogenatmosphere. The reaction was allowed to cool and evaporated to dryness.The residue was suspended in 100 mL of THF and filtered and evaporateddryness. The residue was dissolved in 100 mL of EtOAc and 100 mL of 1NHCl. The reaction mixture was stirred vigorously for two hours. Theorganic layer was separated and evaporated to dryness. The residue wasdissolved in 100 mL of THF and 0.5 g (2.7 mmol) of Et₄ NF-2H₂ O wasadded and the reaction mixture was stirred for sixteen hours at ambienttemperature, under a nitrogen atmosphere. The reaction mixture wasevaporated to dryness and purified by chromatography of a silica gelcolumn eluted with a linear gradient beginning with CHCl₃ and endingwith CHCl₃ --MeOH (4:1)(v/v). This yielded 300 mg of the title compoundisolated as a tan solid, mp: 97-100° C.

PMR: (CDCl₃) δ 1.60 (s br, 2H); 1.80 (s br,4H); 2.80 (s br, 4H); 3.00(t, J=3 Hz, 2H); 3.25 (s, 1H); 4.25 (t, J=3 Hz, 2H); 6.75-6.80 (m,4H);7.25 (d, J=8 Hz, 2H); 7.60 (d, J=10 Hz, 1H); 7.75 (d, J=10 Hz, 2H); 7.85(d, J=10 Hz, 1H); 8.10 (s, 1H); MS: m/e=481 (M⁺) FD; EA: Calc. for C₃₀H₂₇ NO₃ S-H₂ O: C, 72.12; H, 5.85; N, 2.80 Found: C, 72.27; H, 6.11; N,2.66.

TEST PROCEDURE General Preparation Procedure

In the examples illustrating the methods, a post-menopausal model wasused in which effects of different treatments upon circulating lipidswere determined.

Seventy-five day old female Sprague Dawley rats (weight range of 200 to225 g) are obtained from Charles River Laboratories (Portage, Mich.).The animals are either bilaterally ovariectomized (OVX) or exposed to aSham surgical procedure at Charles River Laboratories, and then shippedafter one week. Upon arrival, they are housed in metal hanging cages ingroups of 3 or 4 per cage and have ad libitum access to food (calciumcontent approximately 0.5%) and water for one week. Room temperature ismaintained at 22.2°±1.7° C. with a minimum relative humidity of 40%. Thephotoperiod in the room is 12 hours light and 12 hours dark.

Dosing Regimen Tissue Collection. After a one week acclimation period(therefore, two weeks post-OVX) daily dosing with test compound isinitiated. 17α-ethynyl estradiol or the test compound are given orally,unless otherwise stated, as a suspension in 1% carboxymethylcellulose ordissolved in 20% cyclodextrin. Animals are dosed daily for 4 days.Following the dosing regimen, animals are weighed and anesthetized witha ketamine: Xylazine (2:1, V:V) mixture and a blood sample is collectedby cardiac puncture. The animals are then sacrificed by asphyxiationwith CO₂, the uterus is removed through a midline incision, and a wetuterine weight is determined.

Cholesterol Analysis. Blood samples are allowed to clot at ambienttemperature for 2 hours, and serum is obtained following centrifugationfor 10 minutes at 3000 rpm. Serum cholesterol is determined using aBoehringer Mannheim Diagnostics high performance cholesterol assay.Briefly, the cholesterol is oxidized to cholest-4-en-3-one and hydrogenperoxide. The hydrogen peroxide is then reacted with phenol and4-aminophenazone in the presence of peroxidase to produce a p-quinoneimine dye, which is read spectrophotemetrically at 500 nm. Cholesterolconcentration is then calculated against a standard curve.

Uterine Eosinophil Peroxidase (EPO) Assay. Uteri are kept at 4° C. untiltime of enzymatic analysis. The uteri are then homogenized in 50 volumesof 50 mM Tris buffer (pH--8.0) containing 0.005% Triton X-100. Uponaddition of 0.01% hydrogen peroxide and 10 mM o-phenylenediamine (finalconcentrations) in Tris buffer, increase in absorbance is monitored forone minute at 450 nm. The presence of eosonophils in the uterus is anindication of estrogenic activity of a compound. The maximal velocity ofa 15 second interval is determined over the initial, linear portion ofthe reaction curve.

Source of Compound: 17α-ethynyl estradiol was obtained from SigmaChemical Co., St. Louis, Mo.

The pharmacologic activity for the methods of the current invention,i.e., the compounds of formula I, are illustrate in Table 1, below.

Osteoporosis Test Procedure

Following the General Preparation Procedure, infra, the rats are treateddaily for 35 days (6 rats per treatment group) and sacrificed by carbondioxide asphyxiation on the 36th day. The 35 day time period issufficient to allow maximal reduction in bone density, measured asdescribed herein. At the time of sacrifice, the uteri are removed,dissected free of extraneous tissue, and the fluid contents are expelledbefore determination of wet weight in order to confirm estrogendeficiency associated with complete ovariectomy. Uterine weight isroutinely reduced about 75% in response to ovariectomy. The uteri arethen placed in 10% neutral buffered formalin to allow for subsequenthistological analysis.

The right femurs are excised and digitized x-rays generated and analyzedby an image analysis program (NIH image) at the distal metaphysis. Theproximal aspect of the tibiae from these animals are also scanned byquantitative computed tomography.

In accordance with the above procedures, compounds of the presentinvention and ethynyl estradiol (EE₂) in 20% hydroxypropylβ-cyclodextrin are orally administered to test animals.

                  TABLE 1                                                         ______________________________________                                                                            Serum                                        Dose Uterine Wt. Uterine EPO Cholesterol                                     Compound mg/kg).sup.a (% Inc.).sup.b (Vmax).sup.c (% Dec.).sup.d            ______________________________________                                        EE.sub.2.sup.e                                                                         0.      171.2*     142.4*  85.1*                                       Example 1 0.1 46.9* 4.5 -8.6                                                   1 19.1 4.8 42.5*                                                              10 45.2* 7.5 56.1*                                                           Example 2 0.1 19.4 2.4 -1.2                                                    1.0 16.8 0.0 26.7                                                             10.0 52.5* 4.8 55.6*                                                         Example 3 0.1 11.8 3.3 -2.4                                                    1.0 21.7 3.3 8.7                                                              10.0 47.1* 4.8 58.0*                                                         Example 4 0.1 18.8 3.3 0.6                                                     1.0 27.2 3.0 10.4                                                             10.0 29.6* 3.6 44.9*                                                         Example 5 0.1 18.8 1.2 -6.3                                                    1.0 51.8* 2.1 20.4                                                            10.0 69.4* 5.4 45.4*                                                         Example 6 0.1 14.3 3.9 39.4*                                                   1.0 27.8 4.8 58.7*                                                            10.0 22.5 4.8 65.8*                                                        ______________________________________                                         *p < 0.05                                                                     .sup.a mg/kg PO                                                               .sup.b Uterine Weight, % increase versus the ovariectomized controls          .sup.c Eosinophil peroxidase, V.sub.maximum                                   .sup.d Serum cholesterol decrease versus ovariectomized controls              .sup.e 17Ethynyl-estradiol                                               

As evidence of the current invention treat estrogen dependent cancer,the following assay was performed.

MCF-7 Proliferation Assay

MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM(minimal essential medium, phenol red-free, Sigma, St. Louis, Mo.)supplemented with 10% fetal bovine serum (FBS) (V/V), L-glutamine (2mM), sodium pyruvate (1 mM), HEPES{(N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] 10 mM},non-essential amino acids and bovine insulin (1 ug/mL) (maintenancemedium). Ten days prior to assay, MCF-7 cells were switched tomaintenance medium supplemented with 10% dextran coated charcoalstripped fetal bovine serum (DCC-FBS) assay medium) in place of 10% FBSto deplete internal stores of steroids. MCF-7 cells were removed frommaintenance flasks using cell dissociation medium [Ca++/Mg++ free HBSS(phenol red-free) supplemented with 10 mM HEPES and 2 mM EDTA]. Cellswere washed twice with assay medium and adjusted to 80,000 cells/mL.Approximately 100 mL (8,000 cells) were added to flat-bottommicroculture wells (Costar 3596) and incubated at 37° C. in a 5% CO₂humidified incubator for 48 hours to allow for cell adherence andequilibration after transfer. Serial dilutions of drugs or DMSO as adiluent control were prepared in assay medium and 50 mL transferred totriplicate microcultures followed by 50 mL assay medium for a finalvolume of 200 mL. After an additional 48 hours at 37° C. in a 5% CO₂humidified incubator, microcultures were pulsed with tritiated thymidine(1 μCi/well) for 4 hours. Cultures were terminated by freezing at -70°C. for 24 hours followed by thawing and harvesting of microculturesusing a Skatron Semiautomatic Cell Harvester. Samples were counted byliquid scintillation using a Wallac BetaPlace β counter. The compoundsof formula I are active and potent in inhibiting the tumor cell growth,see: Table 2.

                  TABLE 2                                                         ______________________________________                                               Compound                                                                              IC.sub.50 (nM)                                                 ______________________________________                                               Example 1                                                                             40                                                               Example 2 45                                                                  Example 3 45                                                                  Example 5 60                                                                  Example 6 20                                                                ______________________________________                                    

As used herein, the term "effective amount" means an amount of compoundof the present invention which is capable of inhibiting the symptoms ofthe various pathological conditions herein described. The specific doseof a compound administered according to this invention will, of course,be determined by the particular circumstances surrounding the caseincluding, for example, the compound administered, the route ofadministration, the state of being of the patient, and the pathologicalcondition being treated.

The compounds of this invention can be administered by a variety ofroutes including oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal. These compounds preferably are formulatedprior to administration, the selection of which will be decided by theattending physician. Thus, another aspect of the present invention is apharmaceutical composition comprising an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof.

The total active ingredients in such formulations comprises from 0.1% to99.9% by weight of the formulation. By "pharmaceutically acceptable" itis meant the carrier, diluent, excipients and salt must be compatiblewith the other ingredients of the formulation, and not deleterious tothe recipient thereof.

Pharmaceutical formulations of the present invention can be prepared byprocedures known in the art using well known and readily availableingredients. For example, the compounds of formula I, with or without anestrogen or progestin compound, can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, andpolyvinyl-pyrrolidone; moisturizing agents such as glycerol;disintegrating agents such as calcium carbonate and sodium bicarbonate;agents for retarding dissolution such as paraffin; resorptionaccelerators such as quaternary ammonium compounds; surface activeagents such as cetyl alcohol, glycerol monostearate; adsorptive carrierssuch as kaolin and bentonite; and lubricants such as talc, calcium andmagnesium stearate, and solid polyethyl glycols.

The compounds also can be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for example, by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular physiological location,possibly over a period of time. The coatings, envelopes, and protectivematrices may be made, for example, from polymeric substances or waxes.

Compounds of formula I, alone or in combination with anotherpharmaceutical agent, generally will be administered in a convenientformulation. A typical dosage amount is from about 5 mg to about 600 mg,1 to 3 times a day. More typically, the dose will be about 15 mg to 80mg/day. The term of administration will be for a period of at least 2months. More typically, administration will be at least 6 months, orchronically. The following formulation examples only are illustrativeand are not intended to limit the scope of the present invention.

Formulations

In the formulations which follow, "active ingredient" means a compoundof formula I, or a salt or solvate thereof.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following:

    ______________________________________                                        Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient 0.1-1000                                                      Starch, NF 0-650                                                              Starch flowable powder 0-650                                                  Silicone fluid 350 centistokes 0-15                                         ______________________________________                                    

The formulation above may be changed in compliance with the reasonablevariations provided.

A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets

    ______________________________________                                        Ingredient       Quantity (mg/tablet)                                         ______________________________________                                        Active ingredient                                                                                2.5-1000                                                     Cellulose, microcrystalline 200-650                                           Silicon dioxide, fumed  10-650                                                Stearate acid  5-15                                                         ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 2.5-1000 mg of active ingredientare made up as follows:

Formulation 3: Tablets

    ______________________________________                                        Ingredient         Quantity (mg/tablet)                                       ______________________________________                                        Active ingredient  25-1000                                                      Starch 45                                                                     Cellulose, microcrystalline 35                                                Polyvinylpyrrolidone 4                                                        (as 10% solution in water)                                                    Sodium carboxymethyl cellulose 4.5                                            Magnesium stearate 0.5                                                        Talc 1                                                                      ______________________________________                                    

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 ml dose aremade as follows:

Formulation 4: Suspensions

    ______________________________________                                        Ingredient         Quantity (mg/5 ml)                                         ______________________________________                                        Active ingredient  0.1-1000     mg                                              Sodium carboxymethyl cellulose 50 mg                                          Syrup 1.25 mg                                                                 Benzoic acid solution 0.10 mL                                                 Flavor q.v.                                                                   Color q.v.                                                                    Purified water to 5 mL                                                      ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

An aerosol solution is prepared containing the following ingredients:

Formulation 5: Aerosol

    ______________________________________                                        Ingredient           Quantity (% by weight)                                   ______________________________________                                        Active ingredient    0.25                                                       Ethanol 25.75                                                                 Propellant 22 (Chlorodifluoromethane) 70.00                                 ______________________________________                                    

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

Formulation 6: Suppositories

    ______________________________________                                        Ingredient    Quantity (mg/suppository)                                       ______________________________________                                        Active ingredient                                                                             250                                                             Saturated fatty acid 2,000                                                    glycerides                                                                  ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution

    ______________________________________                                        Ingredient            Quantity                                                ______________________________________                                        Active ingredient       50 mg                                                   Isotonic saline 1,000 mL                                                    ______________________________________                                    

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

Formulation 8: Combination Capsule I

    ______________________________________                                        Ingredient    Quantity (mg/capsule)                                           ______________________________________                                        Active ingredient                                                                           50                                                                Premarin 1                                                                    Avicel pH 101 50                                                              Starch 1500 117.50                                                            Silicon Oil 2                                                                 Tween 80 0.50                                                                 Cab-O-Sil 0.25                                                              ______________________________________                                    

Formulation 9: Combination Capsule II

    ______________________________________                                        Ingredient    Quantity (mg/capsule)                                           ______________________________________                                        Active ingredient                                                                           50                                                                Norethylnodrel 5                                                              Avicel pH 101 82.50                                                           Starch 1500 90                                                                Silicon Oil 2                                                                 Tween 80 0.50                                                               ______________________________________                                    

Formulation 10: Combination Tablet

    ______________________________________                                        Ingredient     Quantity (mg/capsule)                                          ______________________________________                                        Active ingredient                                                                            50                                                               Premarin 1                                                                    Corn Starch NF 50                                                             Povidone, K29-32 6                                                            Avicel pH 101 41.50                                                           Avicel pH 102 136.50                                                          Crospovidone XL10 2.50                                                        Magnesium Stearate 0.50                                                       Cab-O-Sil 0.50                                                              ______________________________________                                    

We claim:
 1. A compound of formula I ##STR6## wherein R¹ is --COOR⁶,--C.tbd.CH, --CH═CH₂, or --COCH₃ ;R² is --H, --Cl, --F, C₁ -C₄ alkyl,--OH, --O(C₁ -C₄ alkyl), --OCO(C₁ -C₆ alkyl), --O--CO--O(C₁ -C₆ alkyl),--O--CO--AR, --OSO₂ (C₂ -C₆ alkyl), or --O--CO--OAR, where AR isoptionally substituted phenyl; R³ and R⁴ are, independently, R² ; R⁵ is1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino; R⁶ is --H or C₁ -C₄ alkyl; Xis --CO-- or --CH₂ --; and n is 2 or 3; with the proviso that when R² is--OH, --O(C₁ -C₄ alkyl), --OCO(C₁ -C₆ alkyl), --O--CO--O(C₁ -C₆ alkyl),or --O--CO--AR, then R¹ is not --COCH₃ ;or a pharmaceutically acceptablesalt or solvate thereof.
 2. A compound according to claim 1 wherein X is--CO--.
 3. A compound according to claim 2 wherein R² is methoxy.
 4. Acompound according to claim 2 wherein R² is hydroxy.
 5. A compoundaccording to claim 1 wherein R⁶ is methyl.
 6. A compound according toclaim 1 wherein R¹ is --C.tbd.CH.
 7. A compound according to claim 1wherein R¹ is acetyl.
 8. A compound according to claim 1 wherein saidcompound is[2-(4-hydroxyphenyl)-6-methoxycarbonylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanonehydrochloride.
 9. A compound according to claim 1 wherein said compoundis[2-(4-hydroxyphenyl)-6-ethynylbenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.10. A method of inhibiting bone loss in a human comprising theadministration of a compound of formula I of claim 1 to a human in needthereof.
 11. A method according to claim 10, wherein said human is apost-menopausal female.
 12. A method of inhibiting a cardiovasculardisease comprising the administration of a compound of formula I ofclaim 1 to a human in need thereof.
 13. A method according to claim 12wherein the cardiovascular disease is hyperlipidemia.
 14. A methodaccording to claim 12 wherein the human being treated is apost-menopausal female.
 15. A method of inhibiting an estrogen-dependentcancer, comprising the administration of a compound of formula I ofclaim 1 to a human in need thereof.
 16. A method according to claim 15wherein the estrogen-dependent cancer is breast cancer.
 17. A methodaccording to claim 15 wherein the said human is a female.
 18. A methodaccording to claim 15 wherein the estrogen-dependent cancer is uterinecancer.
 19. A pharmaceutical formulation comprising a compound offormula I of claim 1, and one or more pharmaceutically acceptableexcipients, carriers, or diluents.
 20. A compound of formula II ##STR7##wherein R^(2a), R^(3a), and R^(4a) are, independently, --H, --Cl, --F,C₁ -C₄ alkyl, or --OR⁷, where R⁷ is a hydroxyl protecting group; andR⁵is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino; X is --CO-- or --CH₂ --; andn is 2 or 3;or a pharmaceutically acceptable salt or solvate thereof.21. A compound according to claim 20 wherein X is --CO--.
 22. A compoundaccording to claim 21 wherein R⁷ is tert-butyldimethylsilyloxy.
 23. Acompound according to claim 20 wherein n is two.
 24. A compoundaccording to claim 23 wherein R⁵ is piperidinyl.
 25. A compoundaccording to claim 20 wherein said compound is[2-[4-(t-butyldimethylsilyloxy)phenyl]-6-trifluoromethylsulfonoyloxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.